The present invention relates to novel compounds which are useful as therapeutic agents for glaucoma.
In general, glaucoma is a disease wherein visual functions suffer disorders caused by a rise of intraocular pressure. Aqueous humor outflow is closely related to the rise of intraocular pressure. When the aqueous humor outflow is disturbed, the intraocular pressure rises. The aqueous humor flows mainly from trabecular meshwork through a Schlemm""s canal outside an eyeball. The aqueous humor outflow can be increased by reducing resistance of the aqueous humor outflow in this trabecular meshwork. Cells which form the trabecular meshwork (trabecular meshwork cells) have sulfhydryl groups. A method of lowering the intraocular pressure has been reported, in which a compound capable of reacting with the sulfhydryl groups is administered so as to make a morphological change in the trabecular meshwork cells and increase the rate of aqueous humor outflow. (Japanese Examined Patent Publication No. 13013/1995). This patent Publication discloses phenoxyacetic acid derivatives, preferably ethacrynic acid as compounds capable of reacting with the sulfhydryl groups.
The method of lowering the intraocular pressure by causing the morphological change in the trabecular meshwork cells is very interesting as a method of treating glaucoma. However, there have not been so many studies of drugs having such a function mechanism yet. A study of creating new drugs in development of therapeutic agents for glaucoma is a very interesting subject.
Accordingly, noting that ethacrynic acid, which is a phenoxyacetic acid derivative having an xcex1,xcex2-unsaturated carbonyl group, has an effect of causing the morphological change in the trabecular meshwork cells and lowering the intraocular pressure, the present inventors synthesized various novel compounds and studied their effects on morphology of the trabecular meshwork cells. As a result, the present inventors found that novel 1,2-diphenyl-2-propen-1-one derivatives, that is, compounds having a 1,2-diphenyl-2-propen-l-one structure as a basic structure and an amino group introduced into their side chain of the benzene ring at the 1st-position, have excellent effects. Thus, the present invention has been completed.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as xe2x80x9cthe present compoundxe2x80x9d as far as there is no proviso), and pharmaceutical compositions containing them as active ingredients: 
wherein R1 is hydrogen, lower alkyl, hydroxy, lower alkoxy or halogen, R2, R3 and R4, being the same or different, are hydrogen or lower alkyl, and . . . is a single bond or a double bond.
The groups defined above are described in detail hereinafter.
The lower alkyl is straight-chain or branched alkyl having one to eight carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, t-butyl or 3,3-dimethylbutyl.
The lower alkoxy is straight-chain or branched alkoxy having one to eight carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or t-butoxy.
The halogen is fluorine, chlorine, bromine or iodine.
When R3 and/or R4 is hydrogen in the present compounds, the amino group can be protected by a protecting group. The protecting group of the amino group is a general protecting group of an amino group such as acyl, ester, substituted lower alkyl or substituted sulfonyl. In detail, examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl or phenylcarbonyl; ester such as lower alkoxycarbonyl, substituted lower alkoxycarbonyl or phenoxycarbonyl; substituted lower alkyl such as allyl, phenyl-lower alkyl or benzoyl-lower alkyl; and substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl. Each phenyl ring of the above-mentioned phenylcarbonyl, phenoxycarbonyl, phenyl-lower alkyl, benzoyl-lower alkyl and phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
Specific examples of preferred protecting groups of the amino group are acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl or benzoyl; ester such as methoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or phenoxycarbonyl; substituted alkyl such as allyl, benzyl, trityl or (4-methoxyphenyl)diphenylmethyl; and substituted sulfonyl such as benzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl or toluenesulfonyl.
When R1 is hydroxy, the hydroxy can be protected by a general protecting group similarly to amino protection.
Salts in the present invention refer to any pharmaceutically acceptable salts and are exemplified by salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid, citric acid or tartaric acid and the like. When there are geometrical isomers or optical isomers in the present compounds, these isomers are also included in the present invention.
The present compounds can be in the form of solvates such as hydrates.
Preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof,
(1a) R1 is a group selected from hydrogen, lower alkyl and halogen; and/or
(2a) R2 is hydrogen; and/or
(3a) both R3 and R4 are lower alkyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (3a) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (1a), (2a) and (3a) in the compounds represented by the general formula [I] or salts thereof.
The most preferred examples of the present compound are the following compounds and salts thereof.
1) 1-[4-[(E)-3-(Dimethylamino)-1-propenyl]phenyl-2-phenyl-2-propen-1-one 
2) 1-[4-[3-(Dimethylamino)propyl]phenyl-2-phenyl-2-propen-1-one 
The present invention also relates to compounds represented by the following general formula [IV], which are synthetic intermediates of the compounds represented by the above general formula [I], and salts thereof: 
wherein R1, R2, R3, R4 and . . . have the same definitions as mentioned above, and  greater than X is  greater than CHOH or  greater than Cxe2x95x90O. When R3 and/or R4 is hydrogen, the amino group can be protected by protecting group(s).
A typical synthetic route of the present compound [I] is shown below. 
The above synthetic route does not represent all methods, but one typical example. Details of specific synthetic methods are described in later Examples.
A synthetic method of the above route is described in detail below.
The aminoalcohol [II] (compound wherein  greater than X is  greater than CHOH in the compound represented by the general formula [IV] and salts thereof) is treated in the presence of an Oxidizing agent (for example, dimethyl sulfoxide (DMSO)) to give the carbonyl compound represented by the formula [III] (compound wherein  greater than X is  greater than Cxe2x95x90O in the compound represented by the general formula [IV] and salts thereof). Next, the compound [III] is condensed with paraformaldehyde in the presence of a secondary amine by Mannich reaction, and then the present compound [I] is obtained by elimination reaction.
When the reactants have a hydroxy group or an amino group in their molecule in the above-mentioned synthetic method, the group can be protected optionally by a suitable protecting group, and the protecting group can also be removed by a conventional method after the reaction.
The present compounds are novel compounds which are unknown in literatures, and are characterized in that the present compounds have a 1,2-diphenyl-2-propen-1-one structure, that is, the compounds have an xcex1,xcex2-unsaturated carbonyl group substituted by two benzene rings, as a basic structure, and an amino group is introduced into a side chain of the benzene ring at the 1st-position.
As described above in the section of xe2x80x9cBackground Artxe2x80x9d, it was reported that ethacrynic acid has an effect of lowering intraocular pressure by making a morphological change in trabecular meshwork cells and increasing the rate of aqueous humor outflow (see Japanese Examined Patent Publication No. 13013/1995). Ethacrynic acid is a phenoxyacetic acid derivative having an xcex1,xcex2-unsaturated carbonyl group. Focusing attention on this chemical structure of ethacrynic acid, the present inventors studied precisely and found that novel compounds exhibiting higher effects are obtained by introducing one benzene ring into the xcex1-position of ethacrynic acid and by further introducing an amino group into the side chain of the other benzene ring.
Administration methods of drugs can be a method of administering active compounds themselves or a method of administering the drugs in the form to be decomposed in vivo and to be converted into the active compounds, namely in the form of prodrugs. Both are widely used. When the present compounds have a hydroxy group or an amino group protected by a suitable protecting group in their molecules, the present compounds can be administered with the hydroxy group or the amino group protected by the protecting group. The present compounds can also be administered after removing the protecting group to convert the protected group into the hydroxy group or the amino group.
In order to study utility of the present compounds, effects of the present compounds on morphology of the trabecular meshwork cells were investigated. Details will be described later in the section of xe2x80x9cPharmacological Testxe2x80x9d, and morphological changes of the trabecular meshwork cells by adding the present compounds were studied by image analysis. As a result, the present compounds exhibited excellent cell morphology change effects on the trabecular meshwork cells. Accordingly, the present compounds are considered to have excellent intraocular pressure-lowering effects.
The present compound is mainly administered parenterally and can also be administered orally. Examples of dosage forms are eyedrops, injections, tablets, capsules, granules and the like. The present compound can be formulated into preparations by conventional methods. For example, eyedrops can be prepared by optionally using an isotonic agent such as sodium chloride or concentrated glycerine; a buffer such as sodium phosphate or sodium acetate; a surfactant such as polyoxyethylenesorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil; a stabilizer such as sodium citrate or disodium edetate; a preservative such as benzalkonium chloride or paraben; or the like. pH can be in a range acceptable for ophthalmic preparations, and it is preferably in a range of 4 to 8. Oral preparations such as tablets, capsules and granules can be prepared by optionally using a diluent such as lactose, starch, crystalline cellulose or vegetable oil; a lubricant such as magnesium stearate or talc; a binder such as hydroxypropylcellulose or polyvinyl pyrrolidone; a disintegrator such as calcium carboxymethylcellulose; a coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or a gelatin film-forming agent.
The dosage of the present compound can be selected suitably depending on symptoms, age, dosage form and the like. In the case of eyedrops, they are instilled once to several times per day with a concentration of 0.001 to 3% (w/v) solution. In the case of oral preparations, the usual daily dosage is 1 to 1000 mg, which can be given in a single dose or several divided doses.